title: Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: role of endogenous opioids.
abstract: BACKGROUND
  Exercise is often prescribed as a therapy for chronic pain. Short-term exercise briefly increases the production of endogenous analgesics, leading to transient antinociception. In limited studies, exercise produced sustained increases in endogenous opioids, sustained analgesia, or diminished measures of chronic pain. This study tests the hypothesis that regular aerobic exercise leads to sustained reversal of neuropathic pain by activating endogenous opioid-mediated pain modulatory systems.
  
  
  METHODS
  After baseline measurements, the L5 and L6 spinal nerves of male Sprague-Dawley rats were tightly ligated. Animals were randomized to sedentary or 5-week treadmill exercise-trained groups. Thermal and tactile sensitivities were assessed 23 h after exercise, using paw withdrawal thresholds to von Frey filaments and withdrawal latencies to noxious heat. Opioid receptor antagonists were administered by subcutaneous, intrathecal, or intracerebroventricular injection. Opioid peptides were quantified using immunohistochemistry with densitometry.
  
  
  RESULTS
  Exercise training ameliorated thermal and tactile hypersensitivity in spinal nerve-ligated animals within 3 weeks. Sensory hypersensitivity returned 5 days after discontinuation of exercise training. The effects of exercise were reversed by using systemically or intracerebroventricularly administered opioid receptor antagonists and prevented by continuous infusion of naltrexone. Exercise increased β-endorphin and met-enkephalin content in the rostral ventromedial medulla and the mid-brain periaqueductal gray area.
  
  
  CONCLUSIONS
  Regular moderate aerobic exercise reversed signs of neuropathic pain and increased endogenous opioid content in brainstem regions important in pain modulation. Exercise effects were reversed by opioid receptor antagonists. These results suggest that exercise-induced reversal of neuropathic pain results from an up-regulation of endogenous opioids.
authors.affiliation: Graduate Interdisciplinary Program in Pharmacology and Toxiciology, The University of Arizona, Tucson, Arizona, USA.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Stagg
authors.forename: Heriberto P
authors.initials: HP
authors.lastname: Mata
authors.forename: Mohab M
authors.initials: MM
authors.lastname: Ibrahim
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Henriksen
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: T
authors.initials: T
authors.lastname: Philip Malan
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000378:metabolism; D004195:Disease Models, Animal; D004744:Enkephalin, Methionine / Q000378:metabolism; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009437:Neuralgia / Q000503:physiopathology* / Q000534:rehabilitation; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D001615:beta-Endorphin / Q000378:metabolism
chemical_list: D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D004744:Enkephalin, Methionine; D009271:Naltrexone; D001615:beta-Endorphin